CHPA Comments on CHPA Comments on Efficacy and Labeling Efficacy and Labeling Issues for OTC Drug Issues for OTC Drug Products Used in the Products Used in the Treatment of Tinea PedisTreatment of Tinea Pedis

CHPA Antifungal Task GroupCHPA Antifungal Task Group

6 May 20046 May 2004

Doug Bierer, PhD Doug Bierer, PhD

Vice President, Regulatory and Scientific Vice President, Regulatory and Scientific AffairsAffairs

Consumer Healthcare Products Association Consumer Healthcare Products Association (CHPA)(CHPA)

Boni E. Elewski, M.D.Boni E. Elewski, M.D.PProfessor of Dermatologyrofessor of DermatologyUniversity of Alabama, University of Alabama, BirminghamBirmingham

Practicing dermatologist: almost 25 yearsPracticing dermatologist: almost 25 years Clinical researcher for over 15 yearsClinical researcher for over 15 years Author of 3 text books on cutaneous fungal Author of 3 text books on cutaneous fungal

infectionsinfections Over 150 publications and 40 book chapters Over 150 publications and 40 book chapters

(mostly on cutaneous fungal infections)(mostly on cutaneous fungal infections) Chaired Guidelines of Care Committee: Chaired Guidelines of Care Committee:

Treatment of Tinea Pedis (and Other Fungal Treatment of Tinea Pedis (and Other Fungal Infections) -- American Academy of DermatologyInfections) -- American Academy of Dermatology

Consultant: CHPA and industryConsultant: CHPA and industry

Tinea PedisTinea Pedis

Common fungal infection caused by Common fungal infection caused by dermatophytesdermatophytes– Most common cause Most common cause T. rubrumT. rubrum

Infectious disease that affects Infectious disease that affects interdigital spaces and contiguous interdigital spaces and contiguous skinskin

Affects up to 70% of populationAffects up to 70% of population– Highly transmissible in communal areas Highly transmissible in communal areas

Presentation of Interdigital Tinea Pedis

Interdigital Tinea Interdigital Tinea PedisPedis Easily recognized by the Easily recognized by the

consumer consumer Consistent symptomsConsistent symptoms

– Itching and burningItching and burning Consistent signs Consistent signs

– ErythemaErythema– Scaling/hyperkeratosisScaling/hyperkeratosis– Fissures/crackingFissures/cracking

Topical OTC Topical OTC TreatmentsTreatmentsfor Tinea Pedisfor Tinea Pedis Large selection of effective OTC Large selection of effective OTC

topical antifungal productstopical antifungal products– MonographedMonographed– NDA switches at full Rx strengthNDA switches at full Rx strength

As effective as Rx topical As effective as Rx topical antifungal productsantifungal products

As safe as Rx topical antifungal As safe as Rx topical antifungal productsproducts

OTC Treatment of Tinea OTC Treatment of Tinea PedisPedis Apply antifungal products once or Apply antifungal products once or

twice per day (as recommended twice per day (as recommended on OTC label)on OTC label)

Duration of treatment: 1 or 4 Duration of treatment: 1 or 4 weeks (as recommended on OTC weeks (as recommended on OTC label)label)

Signs and symptoms generally Signs and symptoms generally improve during or shortly after improve during or shortly after the treatmentthe treatment

Objective of Treatment Objective of Treatment

Eliminate fungus (dermatophyte)Eliminate fungus (dermatophyte)– Resides in superficial layers of skinResides in superficial layers of skin

– Topical antifungals easily reach Topical antifungals easily reach dermatophyte in excess of MICsdermatophyte in excess of MICs

Improvement of Improvement of Signs and SymptomsSigns and Symptoms Itching and burning alleviated Itching and burning alleviated

early in therapyearly in therapy Some clinical signs take longer to Some clinical signs take longer to

improve or may not fully resolveimprove or may not fully resolve– Erythema/inflammationErythema/inflammation– Scaling/hyperkeratosisScaling/hyperkeratosis– FissuresFissures

Healing Dynamics: Healing Dynamics: ErythemaErythema

Inflammation is a response to Inflammation is a response to dermatophyte presence in dermatophyte presence in stratum corneumstratum corneum

As dermatophyte is eliminated, As dermatophyte is eliminated, erythema improveserythema improves

Healing Dynamics: Healing Dynamics: Scaling/HyperkeratosisScaling/Hyperkeratosis

Scaling/hyperkeratosis caused by Scaling/hyperkeratosis caused by presence of dermatophyte in stratum presence of dermatophyte in stratum corneum corneum

Some scaling/hyperkeratosis may not Some scaling/hyperkeratosis may not completely resolve after dermatophyte completely resolve after dermatophyte eliminatedeliminated– Anatomical occlusionAnatomical occlusion– Pre-existing skin conditionsPre-existing skin conditions

Residual scaling/hyperkeratosis is not Residual scaling/hyperkeratosis is not uncommon after elimination of uncommon after elimination of dermatophytedermatophyte

Healing Dynamics: Healing Dynamics: Fissures/CrackingFissures/Cracking Fissures/cracking caused by presence Fissures/cracking caused by presence

of dermatophyte in stratum corneumof dermatophyte in stratum corneum Resolution of fissures/cracking varies Resolution of fissures/cracking varies

individuallyindividually– May be delayed in patients with anatomic May be delayed in patients with anatomic

occlusionocclusion Residual fissures/cracking occasionally Residual fissures/cracking occasionally

persists after elimination of persists after elimination of dermatophytedermatophyte

Study MethodologyStudy Methodology

Microbiological parametersMicrobiological parameters Clinical efficacy parametersClinical efficacy parameters

Microbiological Microbiological ParametersParameters KOH KOH

– Presence or absence of fungal elementsPresence or absence of fungal elements– Fungal elements may be dead or aliveFungal elements may be dead or alive

Fungal cultureFungal culture– Identifies organism by genus and speciesIdentifies organism by genus and species

Mycological Cure = Mycological Cure = Negative KOH + Negative CultureNegative KOH + Negative Culture

Clinical Efficacy Clinical Efficacy ParametersParameters Complete Cure = Mycological cure + Complete Cure = Mycological cure +

nono signs and signs and nono symptoms symptoms Effective Treatment = Mycological Effective Treatment = Mycological

cure + no more than “mild” signs cure + no more than “mild” signs and symptomsand symptoms

0 = absence of signs/symptoms0 = absence of signs/symptoms 1 = mild1 = mild 2 = moderate2 = moderate 3 = severe3 = severe

Defining “Cure”: What Defining “Cure”: What Is Clinically Is Clinically Meaningful?Meaningful?

Dermatophyte is eliminated Dermatophyte is eliminated (mycological cure)(mycological cure)

No more than “mild” signs and No more than “mild” signs and symptoms remain symptoms remain

0 = absence of signs/symptoms0 = absence of signs/symptoms

1 = mild1 = mild

2 = moderate2 = moderate

3 = severe3 = severe

Defining “Cure”: What Defining “Cure”: What Is Clinically Is Clinically Meaningful?Meaningful? Residual erythema, Residual erythema,

scaling/hyperkeratosis and fissures scaling/hyperkeratosis and fissures occasionally persist after elimination of occasionally persist after elimination of dermatophyte dermatophyte – Scaling, hyperkeratosis, fissuring, erythema Scaling, hyperkeratosis, fissuring, erythema

may exist independent of tinea pedis may exist independent of tinea pedis – Treatment of tinea pedis will not make Treatment of tinea pedis will not make

condition of the skin better than prior to condition of the skin better than prior to infectioninfection

Defining “Cure”: What Defining “Cure”: What Is Clinically Is Clinically Meaningful?Meaningful?

Effective Treatment:Effective Treatment: Mycological cure +Mycological cure +

Clinical improvementClinical improvement

Clinical InsightsClinical Insights

Current OTC antifungal drugs Current OTC antifungal drugs deliver safe and effective deliver safe and effective treatmenttreatment

Clinically meaningful endpoint is Clinically meaningful endpoint is effective treatmenteffective treatment

Dose response studies are not Dose response studies are not needed because topical needed because topical antifungals easily reach antifungals easily reach dermatophytes in excess of MICsdermatophytes in excess of MICs

No Concern About No Concern About Dermatophyte Antifungal Dermatophyte Antifungal Drug ResistanceDrug Resistance

Likelihood of dermatophytic Likelihood of dermatophytic resistance to current topical OTC resistance to current topical OTC antifungal drugs is very lowantifungal drugs is very low

When used as directed, topical When used as directed, topical OTC antifungal drugs are very OTC antifungal drugs are very effective at eliminating the effective at eliminating the fungusfungus

Secondary Bacterial Secondary Bacterial InfectionsInfections Rare reports of secondary bacterial Rare reports of secondary bacterial

infections (e.g. cellulitis) associated with infections (e.g. cellulitis) associated with tinea pedis tinea pedis

Presence of dermatophyte may cause Presence of dermatophyte may cause fissures that serve as portals of entry for fissures that serve as portals of entry for secondary bacterial infectionssecondary bacterial infections

Prompt and effective treatment is essentialPrompt and effective treatment is essential OTC topical antifungals are important OTC topical antifungals are important

because they eliminate the dermatophyte, because they eliminate the dermatophyte, to allow the skin to naturally replace itself to allow the skin to naturally replace itself and restore its barrier functionand restore its barrier function

FDA Reported Lack of FDA Reported Lack of Efficacy (LOE)Efficacy (LOE) FDA reports 35% of all adverse events for FDA reports 35% of all adverse events for

topical antifungal agents are lack of topical antifungal agents are lack of efficacy efficacy

Unclear whether reports of LOE were Unclear whether reports of LOE were specifically related to tinea pedis or one of specifically related to tinea pedis or one of other labeled indications (i.e., tinea other labeled indications (i.e., tinea corporis) or another disorder all together corporis) or another disorder all together

To help put these LOE reports into To help put these LOE reports into perspective, CHPA looked at LOE reported perspective, CHPA looked at LOE reported for OTC topical antifungals relative to units for OTC topical antifungals relative to units soldsold

Lack of Efficacy – Lack of Efficacy – An OTC PerspectiveAn OTC Perspective CHPA collected the number of LOE CHPA collected the number of LOE

reports from 7 OTC manufacturers who reports from 7 OTC manufacturers who distribute the vast majority of OTC distribute the vast majority of OTC antifungal products used to treat tinea antifungal products used to treat tinea pedis (1999-2003)pedis (1999-2003)

1468 reports of lack of efficacy1468 reports of lack of efficacy

>180 million total unit packages sold>180 million total unit packages sold

Less than 9 lack of efficacy reports per Less than 9 lack of efficacy reports per million units soldmillion units sold

Proposed OTC Proposed OTC LabelingLabeling

Drug FactsDrug Facts

Directions for UseDirections for Use

Lack of efficacy may be due to some Lack of efficacy may be due to some consumers stopping treatment consumers stopping treatment prematurelyprematurely

Overwhelming consumers with Overwhelming consumers with complicated data should be avoidedcomplicated data should be avoided– Graphs and/or tables on package label are Graphs and/or tables on package label are

confusing to consumersconfusing to consumers Consumers need simple and concise label Consumers need simple and concise label

statements on how to use the product to statements on how to use the product to achieve maximum benefitachieve maximum benefit

Directions: All Directions: All ProductsProducts

““use daily as directed for the use daily as directed for the full full treatment time, even if treatment time, even if symptoms symptoms improveimprove””

Directions for Use:Directions for Use:One-Week ProductsOne-Week Products Labeling should convey lag time Labeling should convey lag time

between completion of treatment between completion of treatment and resolution of symptomsand resolution of symptoms

Helpful to educate consumers on Helpful to educate consumers on what they can expect under this what they can expect under this use conditionuse condition

For One-Week Use For One-Week Use Products Products

““symptoms may continue to symptoms may continue to

improve after 1 week of improve after 1 week of

treatment as the skin treatment as the skin naturallynaturally

replaces itselfreplaces itself””

WarningsWarnings

To address FDA’s concern about To address FDA’s concern about secondary bacterial infection secondary bacterial infection (e.g., cellulitis), we propose (e.g., cellulitis), we propose adding label information about adding label information about when to see a doctorwhen to see a doctor

WarningsWarnings

““New symptoms develop or New symptoms develop or condition worsenscondition worsens” should be ” should be added after the “Stop use and ask added after the “Stop use and ask a doctor if” warning already on a doctor if” warning already on the OTC labelthe OTC label

Proposed Label Proposed Label AdditionsAdditions ““use daily as directed for the full use daily as directed for the full

treatment time, even if symptoms treatment time, even if symptoms improve” improve” (Direction section)(Direction section)

““symptoms may continue to improve symptoms may continue to improve after 1 week of treatment as the skin after 1 week of treatment as the skin naturally replaces itself” naturally replaces itself” (Direction (Direction section)section)

““new symptoms develop or condition new symptoms develop or condition worsens” worsens” (Warning section)(Warning section)

ConclusionsConclusions

Clinical “cure” should be defined Clinical “cure” should be defined as “effective treatment”as “effective treatment”

Dose response studies are not Dose response studies are not needed because topical needed because topical antifungals easily reach antifungals easily reach dermatophytes in excess of MICs dermatophytes in excess of MICs

Dermatophytic resistance is not a Dermatophytic resistance is not a concernconcern

ConclusionsConclusions

Risk of secondary bacterial Risk of secondary bacterial infections is very low infections is very low

OTC topical antifungals play an OTC topical antifungals play an important role by restoring the important role by restoring the barrier function of skin and barrier function of skin and allowing the skin to naturally allowing the skin to naturally replace itself replace itself

ConclusionsConclusions

Proposed enhanced labeling will Proposed enhanced labeling will reinforce consumer compliance reinforce consumer compliance and decrease potential serious and decrease potential serious adverse eventsadverse events

Current OTC products are safe Current OTC products are safe and provide effective treatment and provide effective treatment when used as directedwhen used as directed